Targeting RAS-regulated Signaling Pathways for Improved Cancer Therapy

Speaker Professor Martin McMahon, Cumming-Presidential Professor of Cancer Biology and Senior Director for Preclinical Translation, Huntsman Cancer Institute and Department of Dermatology, University of Utah

Title Targeting RAS-regulated Signaling Pathways for Improved Cancer Therapy

Host Jody Rosenblatt and Jeremy Carlton

 

Abstract The KRAS>RAF>MEK>ERK MAP kinase signaling pathway is central to the initiation of pancreatic ductal adenocarcinoma (PDA). However, to date, pharmacological inhibition of this pathway, either alone or in combination with conventional chemotherapy, has provided no clinical benefit to PDA patients. Interestingly, we previously demonstrated that combined inhibition of MEK1/2 (with trametinib, T) plus inhibition of autophagy (with hydroxychloroquine, HCQ) demonstrated striking anti-tumor effects in preclinical models and in a patient (P1). However, not all patients respond to the T/HCQ therapy regimen, and P1 eventually developed T/HCQ resistant disease. More recently, we have found that either primary or acquired T/HCQ resistance is associated with focal DNA copy number gains on chromosome 8q24 encompassing c-MYC. Indeed, ectopic expression of c-MYC in PDA cell lines rendered them T/HCQ resistant. Interestingly, a CDK4/6 inhibitor, palbociclib (P), also induced autophagy and overrode c-MYC-mediated T/HCQ resistance, such that P/HCQ promoted regression of T/HCQ resistant PDA tumors with elevated c-MYC expression. Finally, P/HCQ treatment of P1 resulted in both a radiographic and a biochemical disease response. These data suggest that elevated c-MYC expression is both a marker and a mediator of T/HCQ resistance, which may be overcome by the use of CDK4 inhibitors in PDA patients.